We hypothesize that subjects with exceptional longevity have a genetic background that provides protection against several age-related diseases. More specifically, we suggest that the presence of favorable genotypes in longevity-genes may serve as buffering mechanisms against the deleterious effect of aging-genes, resulting in the accumulation of deleterious age-related disease genotypes among individuals with extreme lifespan. Studies of genotypic frequencies among different age groups will serve as a starting point in elucidating the complex genetic networks responsible for longevity. Here we propose theoretical arguments for a novel paradigm, and using preliminary data experimentally corroborate our hypotheses. We have comprehensively characterized over 300 Ashkenazi Jewish families with exceptional longevity (defined as survival in good health to at least age 95), and have identified several biological markers that may be causative in their longevity. This cohort is ideal for the study since it is derived from a genetically homogeneous founder population, a characteristic which has already facilitated the successful identification of numerous disease genes. In a preliminary small scale study, we have shown that these subjects and their offspring have 2-3 fold increased polymorphism rates in 2 known longevity-genes regulating lipoprotein, CETP and APOC-3, and decrease in plasma levels. These are known to contribute to large particles size of HDL and LDL, and increase in HDL levels. We have also demonstrated their association with less hypertension, cardiovascular disease, and metabolic syndrome (in offspring of the long-term survivors) and improved cognitive function (in probands). In addition, our buffering hypothesis has been corroborated by the preliminary study. Specifically, we showed that the favorable CETP genotype buffers the deleterious effects of the aging-gene lipoprotein(a) (Lp(a)). We now propose to greatly extend the scope of the preliminary study by using whole-genome, robust high-throughput SNP discovery technology in combination with our computational approach. The aim is to characterize a cluster of genetic markers in known and newly discovered aging pathways. This will enable us to associate the cluster with intermediate plasma phenotypes and with reduced prevalence of age-related diseases. The nature of this association will elucidate the molecular basis of several important age-related diseases, leading, in turn, to novel preventive and treatment strategies for age-related diseases. We expect this research to have a profound impact on morbidity and mortality, and enhance the quality of life for the elderly.